Plasticizers have an important role in our life due to their physical properties, low cost, and wide applications-including lifesaving medical applications. Several questions need to be answered in order to evaluate their safety: 1) Is the hepato- carcinogenicity of DEHP in rats relevant to humans, considering the differences in metabolism of DEHP by these species? and 2) Are the toxicities associated with DEHP a function of the phthalate ester moiety or could other less toxic phthalate esters be substituted for DEHP? An understanding of the mechanism of toxicity of DEHP and its biotransformation should help answer these questions. DEHP, di-(2-ethylhexyl) phthalate, is the most commonly used plasticizer, a known peroxisome proliferator, and a suspected carcinogen. DEHP is leached from plastic by food and blood products, thus most of the U.S. population may be exposed to significant concentrations of this material. Rats and mice fed DEHP developed hepato carcinomas. Peroxisome proliferation has been associated with the development of carcinomas. The broad objective of the proposed research is to investigate the biotransformation and hepatotoxicity of DEHP. Specific studies will investigate the metabolism of DEHP in the rat, with emphasis on the role of cytochrome P-450-mediated omega and omega-1 oxidation, aldehyde dehydrogenase oxidations and peroxisomal beta- oxidation. The relationship between the metabolism of DEHP and hepatic peroxisome proliferation will be examined. The changes in in vivo toxicity will be related to changes in in vitro toxicity in an effort to elucidate the events leading to peroxisome proliferation. These studies may define potential sites for biochemical intervention to reduce the potential health risk.